DESCRIPTION: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KS is still the most common AIDS-defining cancer in HIV-positive individuals, although KS can also occur in HIV-negative individuals. In certain regions of sub-Saharan Africa, KS is the most prevalent cancer. Other immunosuppressed individuals such as transplant patients also develop KS much more frequently than the healthy population. During the previous funding period we had reported that KSHV and the K1 viral protein can activate the PI3K/Akt/mTOR pathway, upregulate angiogenic factors, and protect cells from apoptosis. Our overarching hypothesis is that KSHV viral proteins modulate pro-survival cellular signaling pathways that are also conducive to transformation. In this application, we propose to determine the mechanisms by which KSHV and its viral proteins modulate the PI3K signaling pathway at multiple nodes. Activation of the PI3K/Akt/mTOR signaling pathway is critical for survival of KSHV- infected cells as well as the survival of KS and PEL tumors. We propose to identify novel host factors that are critical for survival of KSHV-infected cells, which may also help identify new proteins involved in cell survival. Furthermore, our preliminary data suggest that KSHV alters cellular metabolic pathways including glycolysis and fatty acid synthesis. We propose to determine how KSHV and its viral proteins alter host cell metabolism to the advantage of the virus. The proposed studies will provide significant and biologically relevant insights into the functions of viral signaling proteins, and may yield a new target for anti-KSHV therapies.